The Impact of High-Flow Nasal Cannula Therapy on Acute Respiratory Distress Syndrome Patients: A Systematic Review

High-flow nasal cannula (HFNC) is a novel oxygenation approach in the management of acute respiratory distress syndrome (ARDS). This systematic review was focused on evaluating current evidence concerning the efficacy of HFNC in ARDS and its comparison with standard treatment approaches. For this review, a systematic search was undertaken in PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Web of Science, Cochrane Library, and Google Scholar to identify relevant studies. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. All those studies that investigated the impact of HFNC on ARDS patients and were published in the English language were included. The literature search from all databases provided 6157 potentially relevant articles from PubMed (n = 1105), CINAHL (n = 808), Web of Science (n = 811), Embase (n = 2503), Cochrane database (n = 930), and Google Scholar (n = 46). After the exclusion of studies that did not fulfill the criteria, 18 studies were shortlisted for the scope of this systematic review. Among the included studies, five focused on HFNC's impact on COVID-19-related ARDS, whereas 13 studies focused on HFNC's impact on ARDS patients. Most studies demonstrated the efficacy of HFNC in managing ARDS, with some studies showing comparable efficacy and higher safety compared to noninvasive ventilation (NIV). This systematic review highlights the potential benefits of HFNC in ARDS management. The findings show that HFNC is effective in reducing the respiratory distress symptoms, the incidence of invasive ventilation, and the adverse events associated with ARDS. These findings can help clinical decision-making processes and contribute to the evidence base for optimal ARDS management strategies.


Introduction And Background
Acute respiratory distress syndrome (ARDS) is a severe form of acute respiratory failure characterized by hypoxemia, dyspnea, and pulmonary infiltrates. ARDS can be defined as a life-threatening condition characterized by poor oxygenation and non-compliant or "stiff" lungs. This condition is often linked with capillary endothelial and alveolar damage. Most of the cases of ARDS are moderate to severe, accounting for 75%, whereas only 25% are mild in nature [1]. Berlin criteria of diagnosis are widely accepted for the classification of ARDS based on PaO 2 /FiO 2 , with 201-300 mmHg being classified as mild ARDS, 101-200 mmHg as moderate, and less than 100 mmHg as severe ARDS [2]. In recent decades, significant improvements have been observed in critical care management. However, ARDS remains a significant concern for global morbidity and mortality [3]. Oxygenation therapy is critical in the management of ARDS. Traditional oxygenation approaches like face masks and nasal prongs have certain limitations like poor oxygenation and discomfort to patients that hinder their applicability. Due to this gap, noninvasive ventilation (NIV) and high-flow nasal cannula (HFNC) oxygen therapy are widely adopted to provide higher inspired oxygen fractions (FiO 2 ). NIV is utilized as an alternative option to invasive mechanical ventilation, especially in cases of acute-on-chronic respiratory failure. However, the use of NIV in cases of ARDS has had mixed results [3,4]. Despite its advantages, NIV has been implicated with several drawbacks such as intolerance and discomfort in patients. These adverse consequences of NIV have been associated with treatment discontinuation in roughly 22% of the patients [5]. Additionally, NIV is not considered a viable option in patients with neurological disorders, which leaves conventional oxygenation treatment for such patients. However, conventional oxygen therapy has its limitations including lack of flow, limited FiO 2 , intolerance, and claustrophobia owing to the application of face masks [6].
HFNC has emerged as a novel approach that has shown promising results in counteracting the potential drawbacks of conventional oxygenation therapies. HFNC delivers high-flow oxygen, which provides several advantages over traditional oxygen delivery methods [7]. HFNC can deliver higher levels of oxygenation, improve ventilation and mucociliary clearance, and provide greater patient comfort and tolerance. HFNC delivers heated and humidified oxygen at a high flow of 50-60 L/min via a wide-bore nasal cannula [8]. The utilization of a high flow of oxygen facilitates the observation of enhanced inspiratory flow amplifications in individuals suffering from hypoxemia, thereby minimizing the dilution of oxygen and ensuring the delivery of an inspired oxygen fraction (FiO 2 ) that closely approximates the predetermined FiO 2 value [9]. A significant benefit conferred by HFNC therapy is its ability to sustain adequate oxygenation throughout the apneic phase following the administration of anesthesia, which effectively circumvents hypoxemia. NIV, on the other hand, is removed at this phase [10]. A prospective study reported that HNFC reduced hypoxemia incidence compared to standard oxygen during the process of laryngoscopic intubation for patients in immediate need of mechanical ventilation [11]. However, subsequent studies did not validate these findings [12,13].
Several physiological benefits have been identified in HFNC therapy including lower inspiratory resistance, diminished dyspnea, and less effort for breathing in patients [14]. HFNC treatment has also demonstrated sustained effects in patients with ARDS [15,16]. Despite the favorable findings reported in these studies, the extent to which this technique can be applied and its generalizability remain uncertain due to certain limitations. These include the restricted focus on the immediate effects of HFNC in a short-term context, low sample size, and selection bias in these studies. Furthermore, indications for HFNC are not as clearly defined as they are for NIV, with a wide range of suggested applications ranging from palliative care situations to pulmonary infections or cardiac failure [17,18]. Several studies have investigated the effectiveness of HFNC in ARDS patients, with varying results. The potential benefits of HFNC therapy in ARDS have generated significant interest among clinicians and researchers, which has led to a growing body of literature on the topic. This review aims to provide a comprehensive analysis of the available evidence on the impact of HFNC therapy on ARDS patients. Specifically, this review will examine the effects of HFNC therapy on oxygenation, respiratory rate, rates of intubation, and mortality in ARDS patients. The review will also explore potential mechanisms of action underlying the beneficial effects of HFNC therapy as well as the limitations and challenges associated with its use in ARDS patients.

Review Methods
The protocols for the current systemic were devised in adherence to the guidelines prescribed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [19].

Search strategy and data sources
For this review, comprehensive research was conducted in several databases to find relevant studies that explored the impact of HFNC oxygen therapy in ARDS patients. We ran separate searches in PubMed, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, and Cochrane Library databases to find relevant studies. The research was undertaken using a combination of different keywords including "high flow nasal cannula oxygen therapy," "high flow nasal oxygen," or "high flow nasal cannula oxygenation" and "respiratory distress syndrome" or "ARDS" (Appendix 1). Related terms, alternatives, and plurals were also considered. Further, we also search Google Scholar and reference sections of the selected studies to increase the body of evidence in this systemic review. We included studies that met the following criteria: (1) studies that included ADRS patients, (2) studies that investigated the impact of HFNC oxygen therapy in ARDS patients, and (3) studies that were published in the English language. Studies that did not assess oxygenation therapy in ARDS were excluded from the scope of this review.

Data collection process
All the matched articles from database searches were transferred to the reference manager (EndNote 20, Thomson Reuters) with the exclusion of duplicate and non-English titles. After that, the endnote file was transferred to Rayyan, a web-based software to expedite the initial screening of the search results [20]. The further process was divided into three stages: (1) the selection of studies based on title and abstract that were eligible for inclusion in the review, (2) a thorough analysis of the eligible articles keeping in view the aim of the review, and (3) further search was refined based on the exclusion and inclusion criteria, and data were obtained in the form of notes regarding the intervention used in studies, the number of participants, and the methods used.

Flow diagram
The study design adheres to the PRISMA flow diagram and protocol [21], which outlines the systematic approach from identifying relevant articles to selecting articles that meet the eligibility criteria for further analysis ( Figure 1).

Included Studies
The literature search from all databases provided 6157 potentially relevant articles from PubMed (n = 1105), CINAHL (n = 808), Web of Science (n = 811), Embase (n = 2503), and Cochrane database (n = 930). Additionally, 46 studies were identified from Google Scholar searches. After the exclusion of duplicate studies and non-English publications, only 5319 records were further analyzed. Based on keywords and abstracts, 3515 publications were removed from the scope of this review. Of the residual corpus of literature, a thorough assessment was performed to identify the 16 most relevant studies for inclusion in the scope of the current review.

Study Characteristics
Out of the 16 studies reviewed, 10 studies investigated HFNC in COVID-19-related ARDS. The remaining six studies assessed the efficacy of HFNC in ARDS patients due to various conditions.

Studies Investigating HFNC in COVID-19-Related ARDS
In the current review, most studies manifested the efficacy of HFNC in the management of ARDS. All studies that investigated COVID-19-related ARDS were retrospective. Nine studies showed that HFNC reduced respiratory complications and was associated with low ARDS-related adverse events, whereas one study showed similar efficacy of noninvasive positive pressure ventilation (NIPPV) and HFNC treatment ( Table 1). Only four studies defined ARDS according to Berlin's criteria of diagnosis [22][23][24][25]. A total of 1662 participants with ARDS were included in COVID-19-related studies, out of which only 290 participants were clearly described as moderate to severe ARDS, whereas 17 patients were characterized as severe ARDS. The remaining 1355 participants were described as COVID-19-related ARDS patients only.  In patients that received HFNC, the mean rate of re-intubation was 46.11% in COVID-19-related ARDS patients. In HFNC-treated ARDS patients, the mean mortality rate was 25.01%. Five studies described the ratio of oxygen saturation (ROX) index to evaluate the success of HFNC. Changes in PaO 2 /FiO 2 (P/F), reintubation required, percentage mortality, ROX index, and cut-off value are described in Table 2.

Studies Investigating HFNC in ARDS Patients
In the current review, six studies assessed HFNC in ARDS patients ( Table 3). Three studies included participants who were either infants or children below the age of 12 years, whereas the other three studies focused on ARDS in adult patients. A total of 307 participants were included in all studies, out of which only 16 were adequately classified as severe ARDS patients, 31 as moderate ARDS patients, and 37 as mild ARDS cases based on the Berlin definition of ARDS. The remaining patients were not classified as mild, moderate, or severe ARDS, rather the authors described them as ARDS or RDS cases. The mean reintubation rate after HFNC was 25.5% in ARDS patients. The mean mortality percentage was 5.66%. All studies reported that PaO 2 /FiO 2 (P/F) was higher after HFNC from the baseline value. Furthermore, the lower P/F indicated a higher risk of HFNC failure. No study used the ROX index to determine the risk of HFNC failure. 2023

Discussion
This review shows that HFNC can improve oxygenation in ARDS patients and be associated with fewer adverse complications compared to other oxygenation approaches. The present review synthesized the recent evidence regarding the HFNC approach for oxygenation in ARDS patients. The review focused on synthesizing the quantitative data and did not perform qualitative data analysis as it was not the scope of the present review. The results showed that HFNC can reduce the incidence of intubation in COVID-related ARDS patients and reduce the risk of mortality. A retrospective study included in the review propagated that a ROX index below 4.94 serves as a predictor for the need for intubation [22]. ROX index is the quotient between pulse oximetry divided by the fraction of inspired oxygen and the respiratory rate. ROX index is a useful indicator to identify patients who are at low risk of HFNC failure and can continue therapy even after 12 hours. Some studies have suggested that the ROX index has the best prediction accuracy [22,37].
The most suitable cutoff point of the ROX index is considered 4.88 after 12 hours of HFNC and was associated with a low risk of mechanical ventilation. However, some studies have disagreed on whether the ROX index is the best predictor of HFNC failure. The main criticism centered around this is that the ROX index does not consider the most common clinical variable such as heart rate and PaO 2 /FIO 2 . An elevated heart rate can potentially serve as an indicator of heightened sympathetic activation attributable to augmented respiratory effort. A recent study demonstrated that a modified ROX index with the incorporation of HR can serve as a better predictor compared to the ROX index alone [38]. A new modified predictor of HFNC failure (Delta POX-HR) has been described by Kansal et al. by incorporating HR and substitution of PF ratio for SF ratio in addition to respiratory rate [39].
The study by Delbove et al. reported that almost 57% of patients were intubated after the initiation of HFNC therapy. Their findings showed that intubated patients had worse outcomes compared to the HFNC-only group. The respiratory rates per minute in ICU and ICU admission rates were worse compared to the HFNConly group [3]. Previously, a meta-analysis of 17 studies showed that HFNC was not linked to a reduced need for intubation [40]. However, these findings were contradicted by Hamou et al. who reported that HFNC can be used as the first line of oxygenation support in ARDS patients and was associated with a low risk of intubation [41]. Delbove et al. also concluded that ARDS characterized by a PaO 2 /FiO 2 below 150 and a respiratory rate exceeding 35 breaths per minute can be considered a prognostic indicator of the need for endotracheal intubation [3].
In contrast to HFNC therapy, both continuous positive airway pressure (CPAP) support and NIV pose discomfort to patients and necessitate substantial man-machine cooperation. The present review did not find any superiority of continuous positive airway pressure (CPAP) and NIV over HFNC. Zhou et al. reported that NIV did not reduce intubation rates in patients with COVID-19-related ARDS compared to HNFC [27]. Similarly, a retrospective study included in this review reported that HFNC can be used in patients who have a prior failure with CPAP and NIV [29]. Due to the better tolerability of HFNC, it has been used in between sessions of NIV to avoid oxygenation impairment. These findings have been shared by Frat et al. who concluded that HFNC improves oxygenation and tachypnea in ARDS patients [33].
Similarly, the efficacy of HFNC has been described in preterm infants as well. A study by Shoemaker et al. showed that there was no difference in adverse outcomes between HFNC and NCPAP [35]. A randomized clinical trial (RCT) by Kadivar et al. showed that HFNC was associated with a higher rate of intubation compared to CPAP [36]. Apart from preterm infants, HFNC has been shown to improve respiratory scale score, COMFORT scale, and oxygenation saturation [34].
An RCT by Coudroy et al. compared HFNC and NIV in immunocompromised patients [42]. Their findings showed that NIV and HFNC had no difference in mortality rate and other secondary outcomes. However, there was a great decrease in discomfort after HFNC compared to NIV. This point demonstrates the superiority of HFNC over NIV as immunocompromised individuals bear a significant amount of pain and discomfort throughout the course of the disease. Another study evaluated prognostic factors for adverse outcomes and mortality in immunocompromised individuals treated with HNFC. Duration of HFNC before intubation has been described as the major factor for mortality along with disease severity. Furthermore, FiO 2 at initiation and SpO 2 after initiation of HFNC can be considered risk factors for intubation [43]. A significant amount of evidence has highlighted that HFNC can be used as the first line of therapy in ARDS patients who require oxygenation [32].  [45]. A case series also reported three cases of severe barotrauma (two pneumothoraces and one pneumomediastinum) related to HFNC therapy [46]. However, the incidence of complications during HFNC is usually rare, with Baudin et al. reporting 0.9 complications per 100 HFNC treatment days [45]. In the present systemic review, we did not find any significant complications related to HFNC treatment.

Conclusions
In conclusion, this systematic review found that HFNC is an efficacious approach to the management of ARDS. The findings of the included studies consistently demonstrated the efficacy of HFNC in the management of ARDS. In the context of COVID-19-related ARDS, the majority of studies showed that HFNC reduced respiratory complications and low rates of ARDS-related adverse events. In the broader context of ARDS, the reviewed studies collectively supported the use of HFNC as an effective intervention. The specific etiologies of ARDS varied among the studies, indicating that HFNC may be beneficial across different underlying conditions leading to ARDS. Overall, the evidence presented in this systematic review suggests that HFNC can be considered a viable treatment option for ARDS, including COVID-19-related ARDS. However, it is important to note that the majority of studies included in this review were observational or retrospective in nature, which may introduce bias and limit the strength of the conclusions. Further welldesigned randomized controlled trials are needed to confirm these. In summary, HFNC shows promise as a potential therapeutic option for ARDS patients. Its noninvasive nature, ability to provide high-flow oxygenation, and favorable outcomes observed in the reviewed studies make it an attractive alternative to traditional oxygen therapy methods. Further research is warranted to optimize its implementation, determine the optimal patient selection criteria, and compare its effectiveness to other interventions for ARDS management.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.